Trilostane Treatment of Cats with Cushing's Disease

Moe is a 13-year old, DSH male neutered cat who was diagnosed recently with pituitary-dependent hyperadrenocorticism (Cushing's disease), based on the results of a dexamethasone screening test, as well as an abdominal ultrasound examination.

He has been diabetic for about 9 months, well regulated on 5 units of glargine insulin BID and a strict low-carbohydrate diet (< 10% of calories as carbs). However, he never regained his youthful attitude and healthy hair coat after the diabetes was regulated, which eventually led to this diagnosis of Cushing's disease. His main clinical signs include very thin skin, mild truncal hair thinning, lethargy, and a grumpy mood.

With the dexamethasone suppression test, the morning baseline cortisol concentration was a bit high 6.1 µg/dl (reference range, 1-3.5 µg/dl), with no suppression 4 or 8 hours after the administration of the dexamethasone (0.1 mg/kg, IV). On ultrasound, he had marked bilateral adrenomegaly with no evidence of adrenal neoplasia.

Based on these results, we started him on trilostane (Vetoryl) at a dose of 30 mg once daily. Over the last 2 weeks on that dose, the owner noticed that the cat will get up and walk around a bit more often, but his wandering is more aimless, almost like he is restless. He has also developed a habit of meowing or howling loudly at odd times.

We just did an ACTH stimulation test to evaluate the trilostane dosage, using a cosyntropin (Cortrosyn) dose of 125 µg, IV.

• Baseline cortisol: 1.5 µg/dl
• 1 hour post-ACTH: 2.1 µg/dl
• 2 hour post ACTH: 1.7 µg/dl

These cortisol results look pretty good to me, although clinically, Moe does not seem much improved. Do we just need to give him more time? What range of cortisol value should I be aiming for, and when should I retest?  I am planning on another ACTH stimulation test in 2 more weeks.

Do you have very much experience with trilostane in cats, and seen these side effects?

My Response:
Starting dose: Trilostane treatment has been reported only in a few cats with hyperadrenocorticism (1-5), but it can be a valuable medical treatment for cats with this disorder. Based on both reported studies and my personal experience, the recommended starting dose in cats with hyperadrenocorticism is 20–30 mg/cat orally per day, administered once daily or divided between feeding times. The daily trilostane dose frequently needs to be adjusted in cats, based upon resolution of clinical signs, serum biochemistry results, and repeat ACTH response testing.

Recheck evaluation times: Cats on trilostane treatment should be evaluated at 2 weeks, 1 month, 2–3 months and every 1–3 months thereafter (3). At each recheck (scheduled at approximately 3–4 hours after the morning trilostane dose), the owner should be questioned and the cat examined. Blood is then collected for routine clinicopathological analyses, and an ACTH response test is performed.

Goal of therapy: Although the ideal target range for the post-ACTH cortisol concentration for cats receiving trilostane has yet to be determined, a post-ACTH cortisol concentration of 1.5-5.0 µg/dl (50–150 nmol/L) should be targeted. In cats with persistent clinical signs and serum cortisol values higher than this range, the dose of trilostane is increased to 30–60 mg/cat per day, administered once daily or divided at the time of feeding. Additional dosage adjustments are made as required, based upon subsequent recheck examinations and ACTH response testing. In some cats, daily doses as high as 90–120 mg have been required to control clinical signs and lower ACTH-stimulated cortisol concentrations into the ideal range.

It's certainly too early to expect to see resolution of the clinical signs. This generally takes at least a month or two before we can expect to see improvement. Does he have diabetic neuropathy? Many of those cats hurt and they can be grumpy due to that.

Follow-up: 4-week update:
At Moe's 4-week recheck (on 30 mg trilostane once daily), the abnormal crying behavior has lessened, although is not gone completely. He has no obvious signs of diabetic neuropathy. The diabetic control is improving and the owner has been able to decrease his insulin from 5 units BID to 2 units BID. However, the cat still has very thin skin and his hair is not growing back yet.

Results of the ACTH stimulation test, done 4 hours after the morning dose:

• Baseline cortisol: 2.5 µg/dl
• 1 hour post-ACTH: 5.6 µg/dl
• 2 hour post ACTH: 4.2 µg/dl

So, looks like so far, so good. I am relieved to finally see some clinical improvement. The current trilostane dose will be continued.

Follow-up: 8-week update
Moe is doing great on the trilostane. He has more energy, and is acting more like his old self. His fur is finally starting to grow back, and his skin is losing that tissue-paper look.

Moe's insulin requirements have continued to drop, and he has been off insulin all together for the last week. He is still eating canned, low-carb food. The owner did a glucose curve at home this week, and his blood sugars ranged from 94 to 130 mg/dl!

Follow-up: 12-week update:
Moe has been on the same dose of trilostane (30 mg once daily) for 12 weeks now, and the owner reports great improvement at home. His attitude is greatly improved, and he is more active and alert. The fur is growing back (mostly), and his skin quality/thickness has improved.

He has been off insulin for the last month. The owner continues to spot check his blood glucose 2-3 times weekly, and she is getting numbers between 80 and 120 mg/dl.

Results of the ACTH stimulation test, done 4 hours after the morning dose:

• Baseline cortisol: 0.6 µg/dl
• 1 hour post-ACTH: 1.3 µg/dl
• 2 hour post ACTH: 1.9 µg/dl

As you can see, these cortisol values are a little lower than his previous tests, but they still look acceptable to me.

My Follow-up Response:
These cortisol values are lower than we'd like.  I'd try decreasing the dose to 20 mg per day (10 mg divided may be best).

Follow-up: 5-month update:
Based on your recommendations, we did decrease the trilostane to 10 mg BID. Within 1 week, however, the owner found that his blood sugar levels, which had previously been in the low-to-mid 100's without insulin, were creeping up above 200 mg/dl and even 300 mg/dl. 

Because of the relapse in his diabetes, we decided to switch him back to the original trilostane dose of 30 mg once daily. Do you agree?

My Follow-up Response:
I wouldn't expect the pancreas to ever really become normal again in Cushing's cats like Moe, in which the diabetes goes into remission after we control the disorder with trilostane.

I'd keep him on this higher dose of trilostane for now and start low dose insulin therapy (e.g., 1-2 U glargine, divided BID).

Follow-up: 7-month update
Moe is doing great again back on the higher dose of the Vetoryl. His blood sugars are all in the normal range, with many readings even below 100 mg/dl, so we are backing him off to 1/2 unit BID and will watch closely.  

Final update:
Since my last post, Moe's diabetes did go back into remission, and his owner says that ever since starting the Vetoryl back in March, Moe did seem to feel much better, so at least we were able to improve his quality of life for a little while.

Last week, however, Moe developed neurologic symptoms (circling) and was admitted to the local teaching hospital. An MRI was performed, and a large pituitary macroadenoma was identified. Because of the poor prognosis, Moe was euthanized.

My Response:
Feline hyperadrenocorticism is a serious disease with a guarded to grave prognosis (3-5). Without treatment, most cats will succumb to complications of the disease within a few weeks to months of diagnosis. The use of trilostane has allowed us to help improve the quality of life for at least some these cats. But some of these cats, like dogs with pituitary-dependent disease, will die of complications related to a pituitary macrotumor (3,4).

More work certainly needs to be done to continue to find better ways to diagnose and treat feline Cushing's syndrome.

References:

1. Boag AK, Neiger R, Church DB. Trilostane treatment of bilateral adrenal enlargement and excessive sex steroid hormone production in a cat. J Small Anim Pract 2004;45:263–266.
2. Neiger R, Witt AL, Noble A, et al. Trilostane therapy for treatment of pituitary-dependent hyperadrenocorticism in 5 cats. J Vet Intern Med 2004;18:160-164.
3. Peterson ME. Feline hyperadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association. 2012;199-203.
4. Cross E, Moreland R, Wallack S. Feline pituitary-dependent hyperadrenocorticism and insulin resistance due to a plurihormonal adenoma. Top Companion Anim Med 2012;27:8-20. 
5. Mellett Keith AM, Bruyette D, Stanley S. Trilostane therapy for treatment of spontaneous hyperadrenocorticism in cats: 15 cases (2004-2012). J Vet Intern Med 2013 (in press).

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